In our previously funded grant we studied the roles of the PI and the Wnt signaling pathways in patients with mood disorders (MD). We found that 5HT2A receptors were increased in the platelets of suicidal patients and patients with MD, PKC isozymes and activity were decreased in patients with bipolar illness, and protein and mRNA expression of BDNF was significantly decreased in the platelets and lymphocytes of patients with MD. Some of these findings need further investigation, especially the physiological significance of decreased BDNF in these patients. During the previous funding period we collected platelets, lymphocytes, neutrophils, and plasma from 40 well-characterized drug-free patients with major depressive disorder (MDD), 40 bipolar manic or mixed (BPM), 40 normal control subjects and from 19 bipolar depressed (BPD) patients. We now propose to study primarily the physiological consequences and the reasons for decreased BDNF in these patients. The physiological effects of BDNF are primarily mediated by PLC, the MAP kinase, and the PI 3-kinase pathways. An abnormal HPA function in depression is one of the most consistent findings in biological psychiatry. HPA function, on the other hand, is also regulated by inflammatory cytokines. Briefly, the specific aims of our proposed studies are as follows. Specific Aim 1. We will determine the protein and mRNA expression of ERK-1, ERK-2, MEK-1, MEK-2, and Ras in the neutrophils of drug-free patients with MD. Specific Aim 2. We will determine the protein and mRNA expression of components of the PI 3-kinase pathway, including PI 3-kinase subunits, and Akt isoforms in the platelets of patients with MD. Specific Aim 3. We will determine the protein and mRNA expression of the glucocorticoid receptors GR and MR and the transcription factors GRE and NF:B in the neutrophils and lymphocytes of patients with MD. Specific Aim 4. We will determine the levels of pro-inflammatory cytokines, namely, IL-12, IL-6, TNF1, CD 40-L and tissue factor, in the plasma of patients with MD. Specific Aim 5. We will examine if the abnormalities in any of the proposed measures are state or trait markers. Specific Aim 6. We will examine the relationship of the proposed markers to dexamethasone suppression test (DST).These studies will test the hypothesis that the functional consequences of the observed decrease in BDNF in MD are related to altered BDNF signaling through the MAP kinase and the PI 3-kinase pathways; and the observed abnormalities of HPA function in depression are related to changes in the feedback mechanism due to alterations of glucocorticoid receptors. Mood disorders are a major public health concern and there is a need for a better understanding not only of the pathophysiology of MD but also the underlying cellular and molecular mechanisms. The proposed research will not only enhance our understanding of the biological abnormalities associated with MD, but may also result in the identification of potentially useful biomarkers for depression and bipolar illness and the detection of more appropriate sites for developing better therapeutic agents for depression and bipolar illness.